This invention relates to methods of treating conditions associated with p38xcex1 and xcex2 kinases and to pyrrolotriazine compounds, more particularly, to pyrrolotriazine carboxamide and benzamide compounds useful for treating p38 kinase-associated conditions.
A large number of cytokines participate in the inflammatory response, including IL-1, IL-6, IL-8 and TNF-xcex1. Overproduction of cytokines such as IL-1 and TNF xcex1 are implicated in a wide variety of diseases, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer""s disease, and congestive heart failure, among others [Henry et al., Drugs Fut., 24:1345-1354 (1999); Salituro et al., Curr. Med. Chem., 6:807-823 (1999)]. Evidence in human patients indicates that protein antagonists of cytokines are effective in treating chronic inflammatory diseases, such as, for example, monoclonal antibody to TNF-xcex1 (Enbrel) [Rankin et al., Br. J. Rheumatol., 34:334-342 (1995)], and soluble TNF-xcex1 receptor-Fc fusion protein (Etanercept) [Moreland et al., Ann. Intern. Med., 130:478-486 (1999)].
The biosynthesis of TNF-xcex1 occurs in many cell types in response to an external stimulus, such as, for example, a mitogen, an infectious organism, or trauma. Important mediators of TNF-xcex1 production are the mitogen-activated protein (MAP) kinases, and in particular, p38 kinase. These kinases are activated in response to various stress stimuli, including but not limited to proinflammatory cytokines, endotoxin, ultraviolet light, and osmotic shock. Activation of p38 requires dual phosphorylation by upstream MAP kinase kinases (MKK3 and MKK6) on threonine and tyrosine within a Thr-Gly-Tyr motif characteristic of p38 isozymes.
There are four known isoforms of p38, i.e., p38xcex1, p38xcex2, p38xcex3, and p38xcex4. The xcex1 and xcex2 isoforms are expressed in inflammatory cells and are key mediators of TNF-xcex1 production. Inhibiting the p38xcex1 and xcex2 enzymes in cells results in reduced levels of TNF-xcex1 expression. Also, administering p38xcex1 and xcex2 inhibitors in animal models of inflammatory disease has proven that such inhibitors are effective in treating those diseases. Accordingly, the p38 enzymes serve an important role in inflammatory processes mediated by IL-1 and TNF-xcex1. Compounds that reportedly inhibit p38 kinase and cytokines such as IL-1 and TNF-xcex1 for use in treating inflammatory diseases are disclosed in U.S. Pat. Nos. 6,277,989 and 6,130,235 to Scios, inc; U.S. Pat. Nos. 6,147,080 and 5,945,418 to Vertex Pharmaceuticals Inc; U.S. Pat. Nos. 6,251,914, 5,977,103 and 5,658,903 to Smith-Kline Beecham Corp.; U.S. Pat. Nos. 5,932,576 and 6,087,496 to G.D. Searle and Co.; WO 00/56738 and WO 01/27089 to Astra Zeneca; WO 01/34605 to Johnson and Johnson; WO 00/12497 (quinazoline derivatives as p38 kinase inhibitors); WO 00/56738 (pyridine and pyrimidine derivatives for the same purpose); WO 00/12497 (discusses the relationship between p38 kinase inhibitors); and WO 00/12074 (piperazine and piperidine compounds useful as p38 inhibitors).
The present invention provides methods of treating conditions associated with p38 kinase activity comprising administering to a patient in need thereof certain pyrrolotriazine compounds. The invention further provides select pyrrolotriazine compounds, including 5-methyl and 5-trifluoromethyl pyrrolotriazine-6-carboxamide compounds useful as kinase inhibitors, particularly kinases p38xcex1 and xcex2. Pyrrolotriazine compounds useful as tyrosine kinase inhibitors are disclosed in U.S. patent application Ser. No. 09/573,829 filed May 18, 2000, assigned to the present assignee. Pyrrolotriazine compounds substituted with an acidic group reportedly having sPLA2-inhibitory activity are disclosed in WO 01/14378 A1 to Shionogi and Co., Ltd, published Mar. 1, 2001 in Japanese. Each of the patent applications, patents, and publications referred to herein is incorporated herein by reference.
The instant invention is directed to methods of treating one or more conditions associated with p38 kinase activity comprising administering to a patient in need thereof one or more pharmaceutically-active compounds having the Formula (I): 
or a pharmaceutically acceptable salt, prodrug, or solvate thereof, wherein:
R3 is hydrogen, methyl, perfluoromethyl, methoxy, halogen, cyano, or NH2;
X is selected from xe2x80x94Oxe2x80x94, xe2x80x94OC(xe2x95x90O)xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94NR10C(xe2x95x90O)xe2x80x94, xe2x80x94NR10C(xe2x95x90O)NR11xe2x80x94, xe2x80x94NR10CO2xe2x80x94, xe2x80x94NR10SO2xe2x80x94, xe2x80x94NR10SO2NR11xe2x80x94, xe2x80x94SO2NR10xe2x80x94, xe2x80x94C(xe2x95x90O)NR10xe2x80x94, halogen, nitro, and cyano, or X is absent;
Z is selected from O, S, N, and CR20, wherein when Z is CR20, said carbon atom may form an optionally-substituted bicyclic aryl or heteroaryl with R4 and R5;
R1 is hydrogen, xe2x80x94CH3, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94SH, xe2x80x94SCH3, xe2x80x94OC(xe2x95x90O)R21, xe2x80x94S(xe2x95x90O)R22, xe2x80x94SO2R22, xe2x80x94SO2NR24R25, xe2x80x94CO2R21, xe2x80x94C(xe2x95x90O)NR24R25, xe2x80x94NH2, xe2x80x94NR24R25, xe2x80x94NR21SO2NR24R25, xe2x80x94NR21SO2R22, xe2x80x94NR24C(xe2x95x90O)R25, xe2x80x94NR24CO2R25, xe2x80x94NR21C(xe2x95x90O)NR24R25, halogen, nitro, or cyano;
R2 is selected from:
a) hydrogen, provided that R2 is not hydrogen if X is xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NR10CO2xe2x80x94, or xe2x80x94NR10SO2xe2x80x94;
b) alkyl, alkenyl, and alkynyl optionally substituted with up to four R26;
c) aryl and heteroaryl optionally substituted with up to three R27; and
d) heterocyclo and cycloalkyl optionally substituted with keto (xe2x95x90O), up to three R27, and/or having a carbonxe2x80x94carbon bridge of 3 to 4 carbon atoms; or
e) R2 is absent if X is halogen, nitro, or cyano;
(i) R4 is substituted aryl, aryl substituted with NHSO2alkyl, substituted heteroaryl, or an optionally-substituted bicyclic 7-11 membered saturated or unsaturated carbocyclic or heterocyclic ring, and R5 is hydrogen, alkyl, or substituted alkyl, except when Z is O or S, R5 is absent, or alternatively,
(ii) R4 and R5 taken together with Z form an optionally-substituted bicyclic 7-11 membered aryl or heteroaryl;
R6 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, xe2x80x94NR7R8, xe2x80x94OR7, or halogen;
R10 and R11 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocyclo, and substituted heterocyclo;
R7, R8, R21, R24, and R25 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocylco, and substituted heterocyclo;
R20 is hydrogen, lower alkyl, or substituted alkyl, or R20 may be absent if the carbon atom to which it is attached together with R4 and R5 is part of an unsaturated bicyclic aryl or heteroaryl;
R22 is alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, or substituted heterocyclo;
R26 is selected from halogen, trifluoromethyl, haloalkoxy, keto (xe2x95x90O), nitro, cyano, xe2x80x94SR28, xe2x80x94OR28, xe2x80x94NR28R29, xe2x80x94NR28SO2, xe2x80x94NR28SO2R29, xe2x80x94SO2R28, xe2x80x94SO2NR28R29, xe2x80x94CO2R28, xe2x80x94C(xe2x95x90O)R28, xe2x80x94C(xe2x95x90O)NR28 R29, xe2x80x94OC(xe2x95x90O)R28, xe2x80x94OC(xe2x95x90O)NR28R29, xe2x80x94NR28C(xe2x95x90O)R29, xe2x80x94NR28CO2R29, xe2x95x90Nxe2x80x94OH, xe2x95x90Nxe2x80x94O-alkyl; aryl optionally substituted with one to three R27; cycloalkyl optionally substituted with keto(xe2x95x90O), one to three R27, or having a carbonxe2x80x94carbon bridge of 3 to 4 carbon atoms; and heterocyclo optionally substituted with keto (xe2x95x90O), one to three R27, or having a carbonxe2x80x94carbon bridge of 3 to 4 carbon atoms; wherein R28 and R29 are each independently selected from hydrogen, alkyl, alkenyl, aryl, aralkyl, C3-7 cycloalkyl, and C3-7 heterocycle, or may be taken together to form a C3-7 heterocycle; and wherein each R28 and R29 in turn is optionally substituted with up to two of alkyl, alkenyl, halogen, haloalkyl, haloalkoxy, cyano, nitro, amino, hydroxy, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy; and
R27 is selected from alkyl, R32, and C1-4 alkyl substituted with one to three R32, wherein each R32 group is independently selected from halogen, haloalkyl, haloalkoxy, nitro, cyano, xe2x80x94SR30, xe2x80x94OR30, xe2x80x94NR30R31, xe2x80x94NR30SO2, xe2x80x94NR30SO2R31, xe2x80x94SO2R30, xe2x80x94SO2NR30R31, xe2x80x94CO2R30, xe2x80x94C(xe2x95x90O)R30, xe2x80x94C(xe2x95x90O)NR30R31, xe2x80x94OC(xe2x95x90O)R30, xe2x80x94OC(xe2x95x90O)NR30R31, xe2x80x94NR30C(xe2x95x90O)R31, xe2x80x94NR30CO2R31, and a 3 to 7 membered carbocyclic or heterocyclic ring optionally substituted with alkyl, halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, amino, or cyano, wherein R30 and R31 are each independently selected from hydrogen, alkyl, alkenyl, aryl, aralkyl, C3-7cycloalkyl, and heterocycle, or may be taken together to form a C3-7heterocycle.
The invention is further directed to compounds having surprisingly advantageous activity as inhibitors of p38 kinases xcex1 and xcex2 and TNF-xcex1 comprising compounds of Formula (II): 
and pharmaceutically acceptable salts, prodrugs or solvates thereof, wherein:
R3 is methyl or CF3;
R5 is hydrogen or alkyl;
Y is xe2x80x94C(xe2x95x90O)NR23xe2x80x94, xe2x80x94NR23C(xe2x95x90O)NR23xe2x80x94, xe2x80x94NR23SO2xe2x80x94, or xe2x80x94SO2NR23xe2x80x94;
R18 and R23 are selected from hydrogen, alkyl, alkoxy, aryl, and aryl substituted with one to three R19, except when Y is xe2x80x94NR23SO2xe2x80x94, R18 is C1-4alkyl or aryl optionally substituted with one to three R19;
R13 and R19 at each occurrence are independently selected from alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, alkylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, and aryloxy, wherein each R13 and/or R19 group may be further substituted by hydroxy, alkyl, alkoxy, aryl, or aralkyl; and
X, R1, R2, and R6 are as defined above for compounds of Formula (I).
Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term xe2x80x9calkylxe2x80x9d refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression xe2x80x9clower alkylxe2x80x9d refers to unsubstituted alkyl groups of 1 to 4 carbon atoms. When a subscript is used with reference to an alkyl or other group, the subscript refers to the number of carbon atoms that the group may contain. The term xe2x80x9cC0-4alkylxe2x80x9d includes a bond and alkyl groups of 1 to 4 carbon atoms.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group substituted by one to four substituents selected from halo, hydroxy, alkoxy, oxo (xe2x95x90O), alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl; alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. SO2NH2, substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g. CONH2, substituted carbamyl e.g. CONHalkyl, CONHaryl, CONHaralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl; alkoxycarbonyl, aryl, substituted aryl, guanidino and substituted or unsubstituted heterocyclos, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where the substituent on the alkyl is further substituted, it will be with alkyl, alkoxy, aryl, or aralkyl.
When the term alkyl is used in connection with another group, as in heterocycloalkyl or cycloalkylalkyl, this means the identified group is bonded directly through an alkyl group which may be branched or straight chain. In the case of substituents, as in xe2x80x9csubstituted cycloalkylalkyl,xe2x80x9d the alkyl portion of the group may, besides being branched or straight chain, be substituted as recited above for substituted alkyl groups and/or the connected group may be substituted as recited herein for that group.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to fluorine, chlorine, bromine and iodine.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups. When the aryl is substituted, each ring of the aryl may be substituted.
The term xe2x80x9csubstituted arylxe2x80x9d refers to an aryl group substituted by one to four substituents selected from alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, and aryloxy. The substituent may be further substituted by hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.
The term xe2x80x9caralkylxe2x80x9d refers to an aryl group bonded directly through an alkyl group, such as benzyl, wherein the alkyl group may be branched or straight chain. In the case of a xe2x80x9csubstituted aralkyl,xe2x80x9d the alkyl portion of the group may, besides being branched or straight chain, be substituted as recited above for substituted alkyl groups and/or the aryl portion may be substituted as recited for substituted aryl. Thus, the term xe2x80x9coptionally substituted benzylxe2x80x9d refers to the group 
wherein each R group may be hydrogen or may also be selected from alkyl, halogen, cyano, nitro, amino, hydroxy, alkoxy, alkylthio, phenyl, benzyl, phenyloxy, and benzyloxy, and other groups recited above. At least two of these xe2x80x9cRxe2x80x9d groups should be hydrogen and preferably at least five of the xe2x80x9cRxe2x80x9d groups is hydrogen. A preferred benzyl group involves the alkyl-portion being branched to define 
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic group for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom and at least one carbon atom-containing ring. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
A xe2x80x9csubstituted heteroarylxe2x80x9d has one to four substituents on any one or more of the rings comprising the heteraryl group. The substituents may be selected from those recited below for heterocycle groups.
Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl 
thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.
Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxaxolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.
Exemplary tricyclic heteroaryl groups include carbazolyl, benzidolyl, phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl and the like.
The term xe2x80x9calkenylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four double bonds.
The term xe2x80x9csubstituted alkenylxe2x80x9d refers to an alkenyl group substituted by one to two substituents selected from halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino, and substituted and unsubstituted heterocycles, including indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
The term xe2x80x9calkynylxe2x80x9d refers to straight or branched chain hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, and most preferably 2 to 8 carbon atoms, having one to four triple bonds.
The term xe2x80x9csubstituted alkynylxe2x80x9d refers to an alkynyl group substituted by a substituent selected from halo, hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl, guanidino and substituted or unsubstituted heterocyclo, e.g. imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a saturated or partially unsaturated non-aromatic cyclic hydrocarbon ring system, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocylic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, cyclodecyl, cyclododecyl, and adamantyl. A xe2x80x9csubstituted cycloalkylxe2x80x9d is substituted with one or more alkyl or substituted alkyl groups as described above, or one or more groups described above as alkyl substituents.
The terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclicxe2x80x9d and xe2x80x9cheterocycloxe2x80x9d each refer to a fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is a 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Thus, the term xe2x80x9cheterocyclexe2x80x9d includes heteroaryl groups as described above. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, and the like.
Exemplary bicyclic hetrocyclic groups include 2,3-dihydro-2-oxo-1H-indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl, and the like.
Also included are smaller heterocyclos, such as epoxides and aziridines.
A xe2x80x9csubstituted heterocyclexe2x80x9d will be substituted with one or more alkyl or aralkyl groups as described above, and/or one or more groups described above as alkyl substituents.
Unless otherwise indicated, when reference is made to a specifically-named heterocyclo or heteroaryl, the reference is intended to include those systems having the maximum number of non-cumulative double bonds or less than that maximum number of double bonds. Thus, for example, the term xe2x80x9cisoquinolinexe2x80x9d refers to isoquinoline and tetrahydroisoquinoline. The term xe2x80x9cdiazepinexe2x80x9d refers to a heterocyclo ring having at least one seven atom ring with two nitrogen atoms in the seven membered ring, including a fully saturated or unsaturated diazepine.
The term xe2x80x9cheteroatomsxe2x80x9d shall include oxygen, sulfur and nitrogen.
The term xe2x80x9chaloalkylxe2x80x9d means an alkyl having one or more halo substituents
The term xe2x80x9cperfluoromethylxe2x80x9d means a methyl group substituted by one, two, or three fluoro atoms, i.e., CH2F, CHF2 and CF3. The term xe2x80x9cperfluoroalkylxe2x80x9d means an alkyl group having from one to five fluoro atoms, such as pentafluoroethyl.
The term xe2x80x9chaloalkoxyxe2x80x9d means an alkoxy group having one or more halo substituents. For example, xe2x80x9chaloalkoxyxe2x80x9d includes xe2x80x94OCF3.
The term xe2x80x9ccarbocyclicxe2x80x9d means a saturated or unsaturated unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon. Thus, the term includes cycloalkyl and aryl rings. The carbocyclic ring may be substituted in which case the substituents are selected from those recited above for cycloalkyl and aryl groups.
When the term xe2x80x9cunsaturatedxe2x80x9d is used herein to refer to a ring or group, the ring or group may be fully unsaturated or partially unsaturated.
Definitions for the various other groups that are recited above in connection with substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted heterocycle, substituted cycloalkyl, and so forth, are as follows: alkoxy is xe2x80x94ORa, alkanoyl is xe2x80x94C(xe2x95x90O)Ra, aryloxy is xe2x80x94OAr, alkanoyloxy is xe2x80x94OC(xe2x95x90O)Ra, amino is xe2x80x94NH2, alkylamino is xe2x80x94NHRa, arylamino is xe2x80x94NHAr, aralkylamino is xe2x80x94NHxe2x80x94Rbxe2x80x94Ar, disubstituted amine or dialkylamino is xe2x80x94NRcRd, alkanoylamino is xe2x80x94NHxe2x80x94C(xe2x95x90O)Ra, aroylamino is xe2x80x94NHxe2x80x94C(xe2x95x90O)Ar, aralkanoylamino is xe2x80x94NHxe2x80x94C(xe2x95x90O)Rbxe2x80x94Ar, thiol is xe2x80x94SH, alkylthio is xe2x80x94SRa, arylthio is xe2x80x94SAr, aralkylthio is xe2x80x94Sxe2x80x94Rbxe2x80x94Ar, alkylthiono is xe2x80x94S(xe2x95x90O)Ra, arylthiono is xe2x80x94S(xe2x95x90O)Ar, aralkylthiono is xe2x80x94S(xe2x95x90O)Rbxe2x80x94Ar, alkylsulfonyl is xe2x80x94SO(q)Ra, arylsulfonyl is xe2x80x94SO(q)Ar, arylsulfonylamine is xe2x80x94NHSO(q)Ar, alkylsulfonylamine is xe2x80x94NHSO2Ra, aralkylsulfonyl is xe2x80x94SO(q)RbAr, sulfonamido is xe2x80x94SO2NH2, nitro is xe2x80x94NO2, carboxy is xe2x80x94CO2H, carbamyl is xe2x80x94CONH2, substituted carbamyl is xe2x80x94C(xe2x95x90O)NHRc or xe2x80x94C(xe2x95x90O)NRcRd, alkoxycarbonyl is xe2x80x94C(xe2x95x90O)ORa, carboxyalkyl is xe2x80x94Rbxe2x80x94CO2H, sulfonic acid is xe2x80x94SO3H, arylsulfonylamine is xe2x80x94NHSO(q)Ar, guanidino is 
and ureido is 
wherein Ra is alkyl as defined above, Rb is alkylene as defined above, Rc and Rd are selected from alkyl, aryl, and aralkyl, Ar is an aryl as defined above, and q is 2 or 3.
Throughout the specification, groups and substituents thereof may be chosen by one skilled in the field to provide stable moieties and compounds.
The compounds of Formula (I) may form salts which are also within the scope of this invention. Pharmaceutically acceptable (i.e. non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolating or purifying the compounds of this invention. All references to compounds of Formula (I) herein are intended to include without limitation compounds of Formulae (Ia) to (Ii) as well as compounds of Formula (II and (IIa)-(IIh). All references to compounds of Formula (II) are intended to include compounds of Formulae (IIa) to (IIh).
The compounds of Formula (I) may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts can be formed as known to those skilled in the art.
The compounds for Formula (I) may form salts with a variety of organic and inorganic acids. Such salts include those formed with hydrogen chloride, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid and various others (e.g., nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts can be formed as known to those skilled in the art.
Salt forms of the compounds may be advantageous for improving the compound dissolution rate and oral bioavailability. For select compounds of Formula (I), mesylate and/or bisulfate salts were successfully obtained (see, e.g., Example 125 herein). Both mesylate and bisulfate salts were found to be non-hygroscopic, highly water soluble, and stable in solid state
In addition, zwitterions (xe2x80x9cinner saltsxe2x80x9d) may be formed.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The definition of compounds according to the invention embraces all the possible stereoisomers and their mixtures. It embraces the racemic forms and the isolated optical isomers having the specified activity. The racemic forms can be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates from the conventional methods, such as, for example, salt formation with an optically active acid followed by crystallization.
Compounds of the Formula (I) may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound for formula I) is a prodrug within the scope and spirit of the invention.
Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p. 309-396, edited by K. Widder, et al. (Acamedic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, xe2x80x9cDesign and Application of Prodrugs,xe2x80x9d by H. Bundgaard, p. 113-191 (1991); and
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992), each of which is incorporated herein by reference.
It should further be understood that solvates (e.g., hydrates) of the compounds of Formula (I) are also with the scope of the present invention. Methods of solvation are generally known in the art.
Preferred embodiments of the invention comprise preferred compounds of Formulae (I) and (II), and methods of treating conditions associated with p38 kinase activity comprising administering preferred compounds of Formulae (I) and (II). Preferred compounds are those having Formula (I), 
and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein:
R3 is methyl, xe2x80x94CF3, or xe2x80x94OCF3,
X is selected from xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94NR10C(xe2x95x90O)xe2x80x94, and xe2x80x94C(xe2x95x90O)NR10xe2x80x94, or X is absent;
Z is N;
R1 is hydrogen, xe2x80x94CH3, xe2x80x94OH, xe2x80x94OCH3, xe2x80x94SH, xe2x80x94SCH3, xe2x80x94OC(xe2x95x90O)R21, xe2x80x94S(xe2x95x90O)R22, xe2x80x94SO2R22, xe2x80x94SO2NR24R25, xe2x80x94CO2R21, xe2x80x94C(xe2x95x90O)NR24R25, xe2x80x94NH2, xe2x80x94NR21SO2NR24R25, xe2x80x94NR21SO2R22, xe2x80x94NR24C(xe2x95x90O)R25, xe2x80x94NR24CO2R25, xe2x80x94NR21C(xe2x95x90O)NR24R25, halogen, nitro, or cyano;
R2 is hydrogen, C2-6 alkyl, substituted C1-4alkyl, aryl, aralkyl, substituted aryl, substituted aralkyl, cycloalkyl, substituted cycloalkyl, heterocycle, or substituted heterocycle, or optionally-substituted cycloalkylalkyl or heterocycloalkyl;
R4 is aryl or heteroaryl substituted with one R12 and zero to three R13;
R5 and R10 independently are selected from hydrogen and lower alkyl;
R6 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, substituted heterocyclo, xe2x80x94NR7R8, xe2x80x94OR7, or halogen;
R12 is carbamyl, sulfonamido, arylsulfonylamine, or ureido, each of which is optionally substituted with up to two of hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, and aralkyl, or R12 is alkylsulfonylamine;
R13 at each occurrence is independently selected from alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, xe2x80x94OR14, xe2x80x94C(xe2x95x90O)alkyl, xe2x80x94OC(xe2x95x90O)alkyl, xe2x80x94NR15R16, xe2x80x94SR15, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R15, xe2x80x94CONH2, xe2x80x94SO3H, xe2x80x94S(xe2x95x90O)alkyl, xe2x80x94S(xe2x95x90O)aryl, xe2x80x94NHSO2-aryl-R17, xe2x80x94NHSO2-alkyl, xe2x80x94SO2NHR17, xe2x80x94CONHR17, and xe2x80x94NHC(xe2x95x90O)NHR17;
R14 is hydrogen, alkyl, or aryl;
R15 is hydrogen or alkyl;
R16 is hydrogen, alkyl, aralkyl, or alkanoyl;
R17 is hydrogen, hydroxy, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, or aralkyl;
R7, R8, R10, R11, R21, R24, and R25 are independently selected from hydrogen and alkyl; and R22 is alkyl or substituted alkyl.
In compounds of Formula (I), preferably the group R3 is methyl, trifluoromethyl, or methoxy, most preferably methyl; X is preferably xe2x80x94CO2xe2x80x94, xe2x80x94NR10C(xe2x95x90O)xe2x80x94, or xe2x80x94C(xe2x95x90O)NR10xe2x80x94, more preferably xe2x80x94C(xe2x95x90O)NHxe2x80x94; Z is preferably N; R4 is preferably substituted aryl or substituted heteroaryl, more preferably phenyl substituted with at least one of carbamyl, substituted carbamyl, arylsulfonylamido, substituted arylsulfonylamido, ureido, or substituted ureido, and optionally substituted with one or two C1-4alkyl or halogen. Most preferably R4 is phenyl substituted with at least one of xe2x80x94C(xe2x95x90O)NHO(C1-4alkyl) or xe2x80x94C(xe2x95x90O)NH(optionally substituted phenyl), and also is optionally substituted with C1-4alkyl. R5 is preferably hydrogen or lower alkyl, more preferably hydrogen.
In preferred compounds, R1 and R6 may be selected from groups of substituents as defined herein; however, advantageously they are selected from hydrogen, CH3, xe2x80x94OH, xe2x80x94OCH3, halogen, nitro, and cyano, and most preferably R1 and R6 are hydrogen. R2 preferably is alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, or substituted heteroaryl, more preferably straight or branched C2-6alkyl or optionally-substituted benzyl. The mesylate salt is the preferred form of salt.
Accordingly, preferred compounds further comprise those having the Formula (II), 
and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein:
R3 is methyl, xe2x80x94CF3, or xe2x80x94OCH3;
X is xe2x80x94C(xe2x95x90O)NR10xe2x80x94, xe2x80x94NR10C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94, or xe2x80x94CO2xe2x80x94;
Y is xe2x80x94C(xe2x95x90O)NHxe2x80x94, xe2x80x94NHC(xe2x95x90O)NHxe2x80x94, or xe2x80x94NHSO2xe2x80x94;
R10 is hydrogen or lower alkyl;
R18 is selected from hydrogen, alkyl, alkoxy, aryl, and aryl substituted with one to three R19, except that when Y is xe2x80x94NHSO2xe2x80x94, R18 is xe2x80x94C1-4alkyl, aryl or aryl substituted with R19;
R13 is attached to any available carbon atom of phenyl ring A and at each occurrence is independently selected from alkyl, substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, xe2x80x94OR14, xe2x80x94C(xe2x95x90O)alkyl, xe2x80x94OC(xe2x95x90O)alkyl, xe2x80x94NR15R16, xe2x80x94SR15, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R15, xe2x80x94CONH2, xe2x80x94SO3H, xe2x80x94S(xe2x95x90O)alkyl, xe2x80x94S(xe2x95x90O)aryl, xe2x80x94NHSO2xe2x80x94aryl-R17, xe2x80x94SO2NHR17, xe2x80x94CONHR17, and xe2x80x94NHC(xe2x95x90O)NHR17;
R14, R15, R16 and R17 are hydrogen or alkyl;
R19 at each occurrence is selected from alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, alkanoyl, alkanoyloxy, thiol, alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, arylsulfonylamine, sulfonic acid, alkysulfonyl, sulfonamido, and aryloxy, wherein each group R19 may be further substituted by hydroxy, alkyl, alkoxy, aryl, or aralkyl;
n is 0, 1 or 2, and
R1, R2 and R6 are as defined above for compounds of Formula (I).
More preferred are compounds having the Formula (IIa) or (IIb): 
and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein:
R3 is methyl;
R1 and R10 are hydrogen or xe2x80x94CH3;
R2 is selected from hydrogen; straight or branched C2-6alkyl; cycloalkyl optionally substituted with keto and/or up to two R27; phenyl optionally substituted with up to two R27; heterocycle optionally substituted with keto and/or up to two R27; and C1-4alkyl substituted with up to three of halogen, trifluoromethyl, cyano, OR28, NR28R29, CO2R28, aryl, heterocycle, and/or cycloalkyl, wherein the aryl, heterocycle, and/or cycloalkyl in turn are optionally substituted with up to two of halogen, hydroxy, alkoxy, haloalkyl, haloalkoxy, nitro, cyano and alkyl;
R18 is hydroxy, C1-4alkoxy, phenyl, or phenyl substituted with one or two R19;
R13 and R19 are selected from lower alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, C1-4alkoxy, nitro, and cyano;
R27 at each occurrence is independently selected from hydrogen, alkyl, trifluoromethyl, trifluoromethoxy, halogen, cyano, nitro, amino, hydroxy, alkoxy, phenyl, benzyl, phenyloxy, and benzyloxy;
R28 and R29 at each occurrence are independently selected from hydrogen, alkyl, alkenyl, phenyl, and benzyl; and
n is 0, 1 or 2.
When R2 is a heterocyclo, advantageously it is selected from diazepinyl, morpholinyl, piperidinyl, and pyrrolidinyl, said heterocycle being optionally substituted with C1-4alkyl, phenyl, and/or benzyl.
Most preferred are compounds having the formula, 
in which R13a and R13b are hydrogen, CH3, OH, OCH3, CF3, cyano, or halogen, R2 is C2-6alkyl or optionally substituted benzyl, R33 is lower alkyl, and n is 0 or 1.
The compounds of the invention are selective inhibitors of p38 kinase activity, and in particular, isoforms p38xcex1 and p38xcex2. Accordingly, compounds of formula (I) have utility in treating conditions associated with p38 kinase activity. Such conditions include diseases in which cytokine levels are modulated as a consequence of intracellular signaling via p38, and in particular, diseases that are associated with an overproduction of cytokines IL-1, IL-4, IL-8, and TNF-xcex1. As used herein, the terms xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d encompass either or both responsive and prophylaxis measures, e.g., designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms. When reference is made herein to inhibition of xe2x80x9cp-38xcex1/xcex2 kinase,xe2x80x9d this means that either p38xcex1 and/or p38xcex2 kinase are inhibited. Thus, reference to an IC50 value for inhibiting p-38xcex1/xcex2 kinase means that the compound has such effectiveness for inhibiting at least one of, or both of, p38xcex1 and p38xcex2 kinases.
In view of their activity as inhibitors of p-38xcex1/xcex2 kinase, compounds of Formula (I) are useful in treating p-38 associated conditions including, but not limited to, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, and viral diseases.
More particularly, the specific conditions or diseases that may be treated with the inventive compounds include, without limitation, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosis, scleroderma, chronic thyroiditis, Grave""s disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn""s disease, psoriasis, graft vs. host disease, inflammatory reaction induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter""s syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic xcex2-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption disease, allograft rejections, fever and myalgias due to infection, cachexia secondary to infection, meloid formation, scar tissue formation, ulcerative colitis, pyresis, influenza, osteoporosis, osteoarthritis and multiple myeloma-related bone disorder, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi""s sarcoma, multiple myeloma, sepsis, septic shock, and Shigellosis; Alzheimer""s disease, Parkinson""s disease, cerebral ischemias or neurodegenerative disease caused by traumatic injury; angiogenic disorders including solid tumors, ocular neovasculization, and infantile haemangiomas; viral diseases including acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS less than ARC or malignancy, and herpes; stroke, myocardial ischemia, ischemia in stroke heart attacks, organ hyposia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, and conditions associated with prostaglandin endoperoxidase syndase-2.
In addition, p38 inhibitors of this invention inhibit the expression of inducible pro-inflammatory proteins such as prostaglandin endoperoxide synthase-2 (PGHS-2), also referred to as cyclooxygenase-2 (COX-2). Accordingly, additional p38-associated conditions include edema, analgesia, fever and pain, such as neuromuscular pain, headache, pain caused by cancer, dental pain and arthritis pain. The inventive compounds also may be used to treat veterinary viral infections, such as lentivirus infections, including, but not limited to equine infectious anemia virus; or retro virus infections, including feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus.
When the terms xe2x80x9cp38 associated conditionxe2x80x9d or xe2x80x9cp38 associated disease or disorderxe2x80x9d are used herein, each is intended to encompass all of the conditions identified above as if repeated at length, as well as any other condition that is affected by p38 kinase activity.
The present invention thus provides methods for treating such conditions, comprising administering to a subject in need thereof an effective amount of at least one compound of Formula (I) or a salt thereof. The methods of treating p38 kinase-associated conditions may comprise administering compounds of Formula (I) alone or in combination with each other and/or other suitable therapeutic agents useful in treating such conditions. Exemplary of such other therapeutic agents include corticosteroids, rolipram, calphostin, CSAIDs, 4-substituted imidazo [1,2-A]quinoxalines as disclosed in U.S. Pat. No. 4,200,750 and in S. Ceccarelli et al, xe2x80x9cImidazo[1, 2-a]quinoxalin-4-amines: A Novel Class of Nonxanthine A1-Adenosine Receptor Antagonists,xe2x80x9d European Journal of Medicinal Chemistry Vol. 33, (1998), at pp. 943-955; Interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors, such as deoxyspergualin (DSG); non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; antiviral agents such as abacavir; antiproliferative agents such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); cytotoxic drugs such as azathiprine and cyclophosphamide; TNF-xcex1 inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians""Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the inventive compounds.
The present invention also provides pharmaceutical compositions capable of treating p38-kinase associated conditions, including TNF-xcex1, IL-1, and/or IL-8 mediated conditions, as described above. The inventive compositions may contain other therapeutic agents as described above and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (e.g., excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques such as those well known in the art of pharmaceutical formulation.
The compounds of Formula (I) may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Topical administration is generally preferred for skin-related diseases, and systematic treatment preferred for cancerous or pre-cancerous conditions, although other modes of delivery are contemplated. For example, the compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; topically, such as in the form of solutions, suspensions, gels or ointments; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion techniques (e.g., as sterile injectable aq. or non-aq. solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.
Exemplary compositions for topical administration include a topical carrier such as PLASTIBASE(copyright) (mineral oil gelled with polyethylene).
Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may also be orally delivered by sublingual and/or buccal administration, e.g., with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL(copyright)) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g., GANTREZ(copyright)); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934(copyright)). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.
The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art, and includes exemplary dosage amounts for a mammal of from about 0.05 to 100 mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats, horses, and the like. Thus, when the term xe2x80x9cpatientxe2x80x9d is used herein, this term is intended to include all subjects, most preferably mammalian species, that are affected by mediation of p38 enzyme levels.
Compounds of formula (I), including the compounds described in the examples hereof, have been tested in one or more of the assays described below and have shown activity as inhibitors of p38xcex1/xcex2 enzymes and TNF-xcex1.
cDNAs of human p38xcex1, xcex2 and xcex3 isozymes were cloned by PCR. These cDNAs were subcloned in the pGEX expression vector (Pharmacia). GST-p38 fusion protein was expressed in E. Coli and purified from bacterial pellets by affinity chromatography using glutathione agarose. p38 fusion protein was activated by incubating with constitutively active MKK6. Active p38 was separated from MKK6 by affinity chromatography. Constitutively active MKK6 was generated according to Raingeaud et al. [Mol. Cell. Biol., 1247-1255 (1996)].
Heparinized human whole blood was obtained from healthy volunteers. Peripheral blood mononuclear cells (PBMCs) were purified from human whole blood by Ficoll-Hypaque density gradient centrifugation and resuspended at a concentration of 5xc3x97106 ml in assay medium (RPMI medium containing 10% fetal bovine serum). 50 ul of cell suspension was incubated with 50 ul of test compound (4xc3x97concentration in assay medium containing 0.2% DMSO) in 96-well tissue culture plates for 5 minutes at RT. 100 ul of LPS (200 ng/ml stock) was then added to the cell suspension and the plate was incubated for 6 hours at 37xc2x0 C. Following incubation, the culture medium was collected and stored at xe2x88x9220xc2x0 C. TNF-xcex1 concentration in the medium was quantified using a standard ELISA kit (Pharmingen-San Diego, Calif.). Concentrations of TNF-xcex1 and IC50 values for test compounds (concentration of compound that inhibited LPS-stimulated TNF-xcex1 production by 50%) were calculated by linear regression analysis.
The assays were performed in V-bottomed 96-well plates. The final assay volume was 60 xcexcl prepared from three 20 xcexcl additions of enzyme, substrates (MBP and ATP) and test compounds in assay buffer (50 mM Tris pH 7.5, 10 mM MgCl2, 50 mM NaCl and 1 mM DTT). Bacterially expressed, activated p38 was pre-incubated with test compounds for 10 min. prior to initiation of reaction with substrates. The reaction was incubated at 25xc2x0 C. for 45 min. and terminated by adding 5 xcexcl of 0.5 M EDTA to each sample. The reaction mixture was aspirated onto a pre-wet filtermat using a Skatron Micro96 Cell Harvester (Skatron, Inc.), then washed with PBS. The filtermat was then dried in a microwave oven for 1 min., treated with MeltilLex A scintillation wax (Wallac), and counted on a Microbeta scintillation counter Model 1450 (Wallac). Inhibition data were analyzed by nonlinear least-squares regression using Prizm (GraphPadSoftware). The final concentration of reagents in the assays are ATP, 1 xcexcM; [xcex3-33P]ATP, 3 nM,; MBP (Sigma, #M1891), 2 xcexcg/well; p38, 10 nM; and DMSO, 0.3%.
Mice (Balb/c female, 6-8 weeks of age, Harlan Labs; n=8/treatment group) were injected intraperitoneally with 50 ug/kg lipopolysaccharide (LPS; E coli strain 0111:B4, Sigma) suspended in sterile saline. Ninety minutes later, mice were sedated by CO2:O2 inhalation and a blood sample was obtained. Serum was separated and analyzed for TNF-alpha concentrations by commercial ELISA assay per the manufacturer""s instructions (RandD Systems, Minneapolis, Minn.).
Test compounds were administered orally at various times before LPS injection. The compounds were dosed either as suspensions or as solutions in various vehicles or solubilizing agents.
For ease of reference, the following abbreviations are employed herein, including the methods of preparation and Examples that follow:
Ph=phenyl
Bz=benzyl
t-Bu=tertiary butyl
Me=methyl
Et=ethyl
Pr=propyl
Iso-P=isopropyl
MeOH=methanol
EtOH=ethanol
EtOAc=ethyl acetate
Boc=tert-butyloxycarbonyl
CBZ=carbobenzyloxy or carbobenzoxy or benzyloxycarbonyl
DCM=dichloromethane
DCE=1,2-dichloroethane
DMF=dimethyl formamide
DMSO=dimethyl sulfoxide
TFA=trifluoroacetic acid
THF=tetrahydrofuran
HATU=O-(7-Azabenzotriazol-1-yl-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronim
hexafluorophosphate
KOH=potassium hydroxide
K2CO3=potassium carbonate
POC13=phosphorous oxychloride
KOtBu=potassium t-butoxide
EDC or EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
DIPEA=diisopropylethylamine
HOBt=1-hydroxybenzotriazole hydrate
m-CPBA=m-chloroperbenzoic acid
NaH=sodium hydride
NaOH=sodium hydroxide
Na2S2O3=sodium thiosulfate
Pd=palladium
Pd/C=palladium on carbon
min=minute(s)
L=liter
mL=milliliter
xcexcL=microliter
g=gram(s)
mg=milligram(s)
mol=moles
mmol=millimole(s)
meq=milliequivalent
RT or rt=room temperature
ret. t.=HPLC retention time (minutes)
sat or sat""d=saturated
aq.=aqueous
TLC=thin layer chromatography
HPLC=high performance liquid chromatography
RP HPLC=reverse phase HPLC
LC/MS=high performance liquid chromatography/mass spectrometry
MS=mass spectrometry
NMR=nuclear magnetic resonance
mp=melting point
In the Examples, xe2x80x9cHPLC Condition Axe2x80x9d refers to YMC S5 ODS 4.6xc3x9750 mm Ballistic column, 4 mL/min flow rate, 4 min linear gradient elution (Start solvent %B=0; Final solvent %B=100), solvent A=10% MeOH/90% H2O/0.2% H3PO4.
Compounds of formula I may generally be prepared according to the following schemes and the knowledge of one skilled in the art. In the schemes, the groups R1-R6, R10, R13, R18, R23, X and Z are as described herein for compounds of Formula (I). 
An optionally substituted 2-formylpyrrole (1) is reacted with an aminating reagent, such as hydroxylamine-O-sulfonic acid, in an aq. solvent at rt, followed by treatment under cooling with a base such as KOH, to form compound (2).
Compound (2) is reacted with an aq. base such as KOH at rt to form compound (3). Compound (3) is reacted with an acylating agent, such as formic acid, in an aq. solvent, to form compound (4). Compound (4) is cyclized with a base such as sodium methoxide in MeOH with heating to form compound (5). Compound (5) is halogenated, e.g., with phosphorus oxybromide at elevated temperature, to form compound (6). Compound (6) is reacted with an amine such as an aniline in an organic solvent, such as acetonitrile, to form product (7) of Scheme 1.
Compound (7) of Scheme 1 where R1=halogen can be prepared from compound (7) of Scheme 1 where R1=hydrogen by reaction with a halogenating agent such as bromine in a suitable solvent such as acetic acid.
Compounds (1) may be obtained from substituted pyrroles by formylation, e.g., by reaction with phosphorus oxychloride and DMF. A methylpyrrole may be obtained by reduction of a formylpyrrole, e.g., by reaction with lithium aluminum hydride. 
Reacting an anion of tosylmethyl isocyanide (TosMIC) (1) with a Michael acceptor such as ethyl crotonate provides disubstituted pyrrole (2). Treatment of pyrrole (2) with an acylating agent such as trichloroacetyl chloride in the presence of a Lewis acid such as aluminum chloride at from rt to 50xc2x0 C., followed by treatment with sodium methoxide, affords trisubstituted pyrrole (3). Compound (3) can be obtained by warming an aldehyde, such as acetaldehyde, with 2 equivalents of ethyl isocyanoacetate in the presence of a base, such as DBU, in an organic solvent, such as THF. Alternatively, compound (3) can be obtained following the procedure of M. Suzuki, M. Miyoshi, and K. Matsumoto J. Org. Chem. 1974, 39 (1980).
Pyrrole (3) can be aminated by an aminating reagent, such as diphenyl phosphoryl hydroxylamine, in the presence of a base, such as NaH, at rt in organic solvents, such as DMF, to form N-aminated pyrrole (4). Compound (4) is cyclized by heating at from 120 to 195xc2x0 C. with formamide to afford 1,2,4-triazine (5). Treatment of compound (5) with a halogenating agent, such as phosphorous oxybromide, at from 60 to 115xc2x0 C., in the presence or absence of a co-solvent such as DCE, affords compound (6).
Compound (6) is reacted with an amine, such as an aniline in an organic solvent, such as DMF, to obtain compound (7). Alternatively, compound (7) can be obtained by treating (6) with an anion of a heterocyclic compound, such as oxindole, in an organic solvent such as THF.
An anion of TosMIC (1) can be made by treating a solution of it in DMSO with a base such as NaH at rt or a solution of it in THF with lithium hexamethyldisilazane at xe2x88x9278xc2x0 C. 
wherein P* protecting group, Rb=R6 described hereinbefore
A suitably N-protected ester of glycine, such as with benzyl group, can be added to dialkyl methylene malonate at from rt to 80xc2x0 C. to obtain compound (1). Compound (1) is cyclized to form pyrrole (2) upon treatment with a strong base, such as lithium hexamethyldisilazane, at from xe2x88x9278xc2x0 C. to rt in an organic solvent such as THF. Pyrrole (2) is alkylated by treatment with an alkylating agent, such as iodomethane or dimethyl sulfate, in the presence of a base, such as K2CO3, in an organic solvent, such as acetone or DMF to yield compound (3).
Deprotection of compound (3) can be achieved, when optionally protected by groups such as benzyl, by hydrogenation over a catalyst, such as Pd, in the presence of ammonium formate. Compound (4) is converted to compound (5) via cyclization as described for compound (5) of Scheme 2.
Hydrolysis of the ester group in compound (5) can be achieved by treatment with a base such as aq. KOH. The resulting acid can be coupled with an amine in the presence of a coupling agent, such as DCC or PyBrop. 
wherein X=NR10, NR10CO, NR10CO, NR10CONR11, NR1COO,
NR10SO2, NR10SO2NR11, as described hereinbefore.
Compound (5) from Scheme 3 can be converted to carboxylic acid (1) (wherein R3 is methoxy or is as otherwise defined herein) by treatment with a base such as aq. KOH. This acid undergoes Curtis rearrangement by treatment with diphenyl phosphoryl azide in the presence of an alcohol, such as benzyl alcohol, in an organic solvent, such as 1,4-dioxane, to afford compound (2).
The carbamate group of compound (2) can be deprotected, when optionally protected by groups such as CBZ, by hydrogenation over a catalyst, such as Pd, to obtain compound (3). The amino group of compound (3) can be acylated to form compound (4), e.g., by treatment with a carboxylic acid in the presence of a coupling agent such as DCC, or sulfonylated, e.g., by treatment with a sulfonyl chloride. Alternatively, the amino group of compound (3) may be alkylated with alkyl halides or may undergo reductive anation with aldehydes in the presence of a reducing agent, such as sodium cyanoborohydride. 
wherein P*=protecting group; Rc, Rd=R6; and R1=H or COOR21 as described hereinbefore.
Suitably protected compound (1) (imino dicarboxylate) can be cyclized by treatment with dialkyl oxalate in the presence of a base, such as sodium methoxide, in an organic solvent, such as MeOH. Compound (2) upon selective deprotection, such as with TFA when optionally protected by tert-butyl ester, undergoes decarboxylation to afford compound (3) where R1=H. This step is omitted to form compound (3) where R1=COOR21.
The hydroxy group of compound (3) can be etherified by reaction with an alkylating agent, such as dimethyl sulfate. Compound (4) can be deprotected by hydrogenation, when optionally protected such as with a benzyl group, to obtain compound (5). Compound (5) is then converted to compound (6) in an analogous manner to that described for compound (4) of Scheme 3 and compounds (4) through (7) of Scheme 2. 
Compound (6) of Scheme 2 can be etherified at the 4-position, e.g., by treatment with phenoxide anion to form compound (1). Reduction of compound (1) with a reducing agent, such as DIBAL, in an organic solvent, such as toluene, affords alcohol (2). Oxidation of the alcohol (2) can be achieved by treatment with MnO2 at an elevated temperature in an organic solvent, such as toluene, to form (3). Treatment of compound (3) with an oxidant, such as m-CPBA in an organic solvent, such as DCM, followed by aq. hydrolysis with a base, such as potassium bicarbonate, affords the hydroxy compound (4).
Alkylation of the phenolic group of compound (4) with an agent, such as iodomethane, in the presence of a base, such as NaH, at from rt to 100xc2x0 C., affords compound (5). Hydrolysis of compound (5) can be achieved by treatment with an acid, such as aq. HCl, at an elevated temperature to afford (6). Compound (6) can be converted to compound (7) with procedures analogous to those described in Scheme 2. 
wherein Rf, Rg=R2 as described hereinbefore
Compound (3) from Scheme 6 can undergo a Wittig reaction, e.g., with phosphonates such as methyl diethylphosphonoacetate, in an organic solvent, such as DCE, in the presence of a base, such as NaH, to afford compound (1). The double bond of compound (1) can be hydrogenated by treatment with hydrogen in the presence of a catalyst, such as Pd. Compound (2) can be converted to (3) by procedures described in Scheme 2.
Hydrolysis of the ester, as described hereinbefore, followed by coupling of the resulting acid with an amine in the presence of a coupling agent, such as DCC, affords compound (4). 
Commercially-available compound (1) can be reacted with oxalyl chloride with heating and then concentrated in vacuo and reacted with an amine R18NH2 in the presence of a base, such as diisopropylamine, in an organic solvent, such as DCM to yield compound (2). Compound (2) can be reacted with hydrogen in the presence of a catalyst, such as Pd, in an alcoholic solvent, such as EtOH, at rt to afford compound (3). Compound (3) can then be used as in Scheme 9 to produce compounds (6) of Scheme 9.
3-methyl-1-pyrrole-2,4-diethyl ester can be reacted with chloramine in ether to produce compound (1). Reacting compound (1) in formamide with acetic acid produces compound (2). Compound (2) can be reacted with DIPEA and POCl3 in toluene to produce compound (3). Compound (3) can be reacted with DIPEA and compound (4) in DMF to produce compound (5). Compound (5) can be reacted in THF with NaOH to produce an acid intermediate which upon treatment with HOBt, EDCI and the appropriate amine (NR2R10) in DMF produces compounds (6).
Compound (4) can be prepared by 1) reacting commercially-available 4-amino-3-methylbenzoic acid and N-(tert-butoxycarbonyl)anhydride in THF to produce a BOC-protected aniline intermediate; 2) reacting the aniline intermediate with -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBt, and DMF, followed by addition of methoxyamine hydrochloride and DIPEA to produce a BOC-protected N-methoxyamide intermediate; and 3) reacting that methoxyamide intermediate in a solution of HCl in dioxane to produce compound (4) as a hydrochloride salt. Alternatively, compound (4) can be prepared as shown in Scheme 8.
A substituted hydroxamate (1) can be reacted with acid, such as HCl, in anhydrous MeOH, to afford compound (2). Compound (2) can be reacted with an aq. base such KOH with heating to form compound (3). Compound (3) is reacted with an amine R18NH2 in the presence of a coupling reagent, such as HATU, and a base such as diisopropylamine, in an organic solvent, such as N-methylpyrrolidinone to afford compounds (4). Alternatively, compounds (4) may generally be prepared as outlined in Schemes 8 and 9. 
Commercially-available compound (1a) can be reacted with a sulfonyl chloride in the presence of a base, such as TEA, in an organic solvent, such as DCM to yield compound (2). Reaction of compound (2) with hydrogen in the presence of a catalyst, such as Pd in a solvent, such as MeOH, yields compound (3). Reaction of compound (3) with chloride (5) (compound 3 of scheme 9) in an organic solvent, such as DMF, at rt affords compound (6).
Reaction of compound (6) with aq. KOH with heating affords compound (7). Compound (7) can be reacted with an amine R2NH2 in the presence of a coupling reagent, such as EDCI, and a base such as diisopropylamine, in an organic solvent, such as DMF to afford compound (8). 
Chloropyrrolotriazine (1) (compound 3 of Scheme 9) can be reacted with an aniline (1a) (e.g., compound 1 of Scheme 11) in anhydrous DMF at rt to afford compound (2). Reaction of compound (2) with an aq. base such as NaOH with heating affords compound (3). Compound (3) can be reacted with an amine R2NH2 in the presence of a coupling reagent, such as HOBt, with or without a base such as diisopropylamine, in an organic solvent, such as DMF to afford compound (4). Compound (4) can be reacted with hydrogen in the presence of a catalyst, such as Pd/C, in an organic solvent, such as MeOH to afford compound (5). Reaction of compound (5) with an isocyanate in an organic solvent, such as DCE affords compound (6). 
Commercially-available compound (1a) (compound 1a of Schemes 11 and 12), can be reacted with carbonyl diimidazole and with an amine R18NH2 in an organic solvent, such as DCE, to yield compound (8). Reaction of compound (8) with hydrogen in the presence of a catalyst, such as Pd, in an alcoholic solvent such as EtOH affords compound (9). Reaction of (9) with chloride (1) in an organic solvent, such as DMF, affords compound (10). Reaction of (10) with aq. NaOH with heating affords product (11). Product (11) can be reacted with an amine R2NH2 in the presence of a coupling reagent, such as EDCI, and a base such as diisopropylamine, in an organic solvent, such as DMF to afford compound (7). 
Glycine ethyl ester can be added to an alkyl alkoxy methylene cyanoacetate at from rt to 80xc2x0 C. to obtain compound (1). Compound (1) is cyclized to form pyrrole (2) upon treatment with a strong base, such as lithium hexamethyldisilazane, at from xe2x88x9278xc2x0 C. to rt in an organic solvent such as THF. Pyrrole (2) is converted to a halide using sodium nitrite in an organic solvent, such as DMF, and a halide source, such as CuBr to yield compound (3). Compound (3) can be converted to compound (4) using CuCN in an organic solvent such as NMP at elevated temperatures. Alternatively, compound (2) can be directly converted to compound (4) using sodium nitrite in an organic solvent, such as DMF, and a cyanide source such as CuCN. Compounds (3) and (4) can then be used as described in previous schemes (e.g., as compound 3 of Scheme 2), to form compounds of Formula (I) wherein R3 is halogen or cyano.
In addition, other compounds of formula I may be prepared using procedures generally known to those skilled in the art. In particular, the following examples provide additional methods for the preparation of the compounds of this invention.
The invention will now be further described by the following working examples, which are preferred embodiments of the invention. HPLC purifications were done on C18 reverse phase (RP) columns using water MeOH mixtures and TFA as buffer solution. These examples are illustrative rather than limiting. There may be other embodiments that fall within the spirit and scope of the invention as defined by the appended claims.